Microwave-assisted flow synthesis

Figure n.2 A metal thin film microcapillary reactor for microwave-assisted flow synthesis. (Reproduced with permission from Ref. [16b]. Copyright Wiley-VCH Verlag GmbH.)... 

In this chapter we discuss the new speeding-up techniques, optimized during the last decade, such as solid-phase extraction, polymer-assisted solution-phase synthesis, microwave-assisted organic synthesis, and flow chemistry. The improvements obtained with these techniques are not limited to a subset of chemical reactions (e.g., the reported examples), but they are fully applicable to the entire set of chemistry involved in the synthetic drug discovery process. 

Organ and coworkers developed a microwave-assisted flow system, which was used successfully for the synthesis of a key intermediate of the ICMT (isoprenylcysteine carboxylmethyltransferase) inhibitor aplysamine 6 (Scheme 1.33) [89]. 

In addition to flow systems that use conventional heating, microwave-assisted flow chemistry has also been reported [78,86-88]. Organ reported the synthesis of benzimidazole through microwave-assisted flow chemistry (Scheme 1.16) [86]. One of the critical components of the flow system was a silicon carbide reactor tube. As mentioned previously, these materials have a very high absorption of microwave radiation and heat very rapidly upon irradiation. The ability of the silicon carbide to transfer heat is also very high thus, this material is ideally suited for the constraction of a reactor tube that wiU be used... 

SCHEME 1.16 Benzimidazole synthesis through microwave-assisted flow chemistry [86]. 

Baxendale IR, Griffiths-Jones CM, Ley SV, Tranmer GK (2006b) Microwave-assisted Suzuki coupling reactions with an encapsulated palladium catalyst for batch and continuous-flow transformations. Chem Eur J 12 4407-4416 Baxendale IR, Deeley J, Griffiths-Jones CM, Ley SV, Saaby S, Tranmer GK (2006c) A flow process for the multi-step synthesis of the alkaloid natural product oxomaritidine a new paradigm for molecular assembly. J Chem Soc Chem Commun 2566-2568... 

Comer, E. and Organ, M.G. (2005). A Microreactor for Microwave-Assisted Capillary (Continuous Flow) Organic Synthesis. J. Am. Chem. Soc., 127, 8160-8167. 

Glasnov, T. N. and Kappe, C.O. (2007). Microwave-Assisted Synthesis under Continuous-Flow Conditions. Macrorwo/. Rqp/JCoOTOTMW., 28, 395-410. 

Shore, G. and Morin, S. and Organ, M.G. (2006). Catalysis in Capillaries by Pd Thin Films Using Microwave-Assisted Continuous-Flow Organic Synthesis (MACOS). Angew. Chem. Int. Ed., 45, 2761-2766. 

Bremner WS, Organ MG (2007) Multicomponent reactions to form heterocycles by microwave-assisted continuous flow organic synthesis. J Comb Chem 9(1) 14—16... 

The scale-up of microwave-assisted reactions is of significant interest to many industrial laboratories. Scale-up can be accomplished in different ways, and these methods are presented in more detail in the following section. After an initial discussion of batch synthesis we will present the currently commercially available instrumentation for flow processing, which can be divided into SF or CF techniques. 

Organ and co-workers [120] described a unique approach to MCRs using a microwave-assisted, continuous flow process for the synthesis of new series of tetrahydro-pyrazolo[3,4-6]quinolin-5(6//)-ones 79. An aldehyde, dimedone, and 5-amino-3-methyl-l//-pyrazole were reacted, yielding the desired compound 79 in moderate to excellent yields. It was proved that the electronic properties of the substituted benzaldehydes have an important impact on the conversions as with electron-donating groups rather low yields were obtained (Scheme 60). 

Shore G, Yoo W-J, Li C-J et al (2009) Propargyl amine synthesis catalysed by gold and copper thin films by using microwave-assisted continuous-flow organic synthesis (MACOS). ChemEur J 16 126-133... 

As is the case with ceramic sintering, joining, and powder synthesis, microwave-assisted fabrication of ceramic coatings can offer unique benefits. To expose the material surfaces for reaction with a gas phase, fibers or powder particles may be suspended by the flow of gas in the fluidized bed. In addition to the flow of the fluidizing gas, low frequency mechanical vibrations (for example, 10-15 Hz) may be applied to the container to reduce the tendency for the powders or fibers to sinter together to form clumps. As the powder size decreases, the powder s sinterability increases. While vibration may not be necessary for particles as large as, say, 50 pm, it may be beneficial for powder particles that are a few microns in diameter. 

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